US20060254583A1 - Dry powder inhaler system - Google Patents

Dry powder inhaler system Download PDF

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US20060254583A1
US20060254583A1 US10/549,124 US54912404A US2006254583A1 US 20060254583 A1 US20060254583 A1 US 20060254583A1 US 54912404 A US54912404 A US 54912404A US 2006254583 A1 US2006254583 A1 US 2006254583A1
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Prior art keywords
container
piercing
pierced
dry powder
end portions
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Arthur Deboeck
Philippe Bauduer
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GALEPHAR PHARMACEUTICAL RESEARCH Inc
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GALEPHAR PHARMACEUTICAL RESEARCH Inc
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Publication of US20060254583A1 publication Critical patent/US20060254583A1/en
Assigned to GALEPHAR PHARMACEUTICAL RESEARCH, INC. reassignment GALEPHAR PHARMACEUTICAL RESEARCH, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BAUDIER, PHILIPPE, VANDERBIST, FRANCIS, DEBOECK, ARTHUR
Priority to US12/656,744 priority Critical patent/US20100300440A1/en
Priority to US14/642,134 priority patent/US20150231344A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/003—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using capsules, e.g. to be perforated or broken-up
    • A61M15/0033—Details of the piercing or cutting means
    • A61M15/0035—Piercing means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0001—Details of inhalators; Constructional features thereof
    • A61M15/0021—Mouthpieces therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/003—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using capsules, e.g. to be perforated or broken-up
    • A61M15/0033—Details of the piercing or cutting means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/064—Powder

Definitions

  • the present invention relates to a pharmaceutical composition for inhalation, consisting in a combination of (A) a dry powder formulation containing a micronized active ingredient, alone or mixed with an inactive ingredient, said powder being filled in a hydroxypropylmethylcellulose (HPMC) capsule and (B) a single dose dry powder inhaler device especially adapted to said capsule to provide a high respiratory dose of said active ingredient when said drug is inhaled by the mouth through said device.
  • Said device being characterized in that he is equipped with piercing needles or pins (in order to pierce the capsule) of diameter of not less than 0.8 mm preferably not less than 1 mm.
  • Capsules, and essentially hard gelatin capsules are very widely used in the pharmaceutical industry to allow oral administration of drugs.
  • Hard gelatin capsules were developed as an edible container to mask the taste and odour of medicines.
  • capsules have become one of the most popular dosage forms for pharmaceuticals.
  • Capsules have traditionally been used for powder or granule formulations, but later have been adapted to contain oily liquids, tablets and even powders for inhalation.
  • Capsules enjoy widespread popularity because of their relative ease of manufacture (compared with other dosage forms such as tablets) and flexibility of size to accommodate a range of fill weights. They are readily able to achieve bioequivalence between different strengths of the same formulation.
  • Hard gelatin capsules do have some drawbacks.
  • the main material used for this purpose generally contains 13-15% water and therefore may not be suitable for use with water sensitive drugs or drug composition.
  • Some drugs may react with the amino groups of gelatin, causing discolouration or formation of crosslinks between gelatin molecules which retard capsule dissolution.
  • Gelatin products are sometimes shunned as a result of religious or vegetarian dietary restrictions.
  • Hard gelatin capsules capsules have also been used since about 25 years to administer powder for inhalation. In this case, the capsule is pierced using an adequate inhalation device and the powder is inhaled via the mouth or sometimes via the nose.
  • hard gelatin capsules are their relatively high water content (13-16%), their animal origin, their brittleness characteristics and the fact that they may chemically or physically interact with some active or inactive ingredients.
  • HPMC capsules hydroxypropylmethylcellulose
  • HPMC capsules will be defined as pharmaceutically acceptable capsules containing at least 70% by weight of hydroxyppropylmethylcellulose.
  • HPMC capsules useful for pharmaceutical applications are described in U.S. Pat. No. 5,756,123.
  • Those HPMC capsules are of vegetal origin and contain 79.6-98.7% by weight of hydroxypropylmethylcellulose, 0.03-0.5% by weight of carrageenan and 0.14-3.19% by weight of a potassium and/or calcium ion.
  • U.S. Pat. No. 5,715,810 describes a device for oral or nasal inhalation of finely divided materials such as medicinal agents and drugs placed in a hermetically sealed container.
  • EP606486 describes a pharmaceutical preparation for inhalation comprising a powdered preparation for intra-tracheal administration contained in a container made for a material mainly comprising at least one compound of the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, starch, hydroxypropylated starch and sodium alginate. According to said document, less adhesion or absorption of the drug will be achieved in said container, with respect to receptacles made of gelatin, polypropylene, aluminum foil or glass.
  • Tests made by applicant have shown that when using conventional dry inhalation system with conventional piercing system, after inhalation, the amount of drug still present in the HPMC capsule (about 20% of the drug initially present in the capsule) was substantially equal to the amount of drug still present in the gelatine capsule (about 18% of the drug initially present in the capsule). Tests made by Applicant have also shown that when using a conventional inhaler system, the lung deposition was better when using a gelatin capsule, instead of a HPMC capsule.
  • HPMC capsules are odourless and flexible, and exhibit similar dissolution behaviour to the gelatin capsule. Their appearance is similar, except that it lacks the lustre of gelatin.
  • the physical properties of both HPMC and gelatin capsule shells that may affect stability and dissolution, and therefore their suitability for use with various formulations and intended use, are listed in Table I. TABLE 1 Comparative characteristics of HPMC capsules and hard gelatin capsules HPMC Gelatin capsules capsules Moisture content 2-5% 13-15% Water vapour permeability Low Low Substrate for protease No Yes Maillard reaction with drug fill No Yes Deformation by heat Above ⁇ 80° C. Above ⁇ 60° C. (degradation) Water dissolution at room Soluble Soluble temperature Static Low High Light degradation No Possible
  • capsule shell hardness There are two components of capsule shell hardness—brittleness and tolerance to deformation—which determine suitability for use with automated encapsulating machines, as well as end use.
  • moisture content of the capsule shell is decreased, as may occur when a desiccant is added to a package of capsules containing moisture-labile drugs, gelatin capsules tend to become brittle and are subject to breakage during transport and storage.
  • the relationship between brittleness and moisture content can be determined using a hardness tester. The results of the testing show that the percentage of broken gelatin capsules sharply increases as the moisture content of the hard gelatin shell drops below 10%, although the degree of brittleness can be modified somewhat by addition of polyethylene glycol (PEG) during manufacture. In contrast, this problem is not observed in HPMC capsule shells even at moisture levels close to 0%.
  • PEG polyethylene glycol
  • DPIs Dry Powder Inhalers
  • MDIs Metered Dose Inhalers
  • CFCs chlorofluorocarbon
  • DPI devices may be either single dose or multidose.
  • the drug is pre-packaged in capsules or blisters.
  • the multidose DPI formulations involve a device containing at least a reservoir and a metering chamber to administer an accurate dose of the drug.
  • a large number of patent applications are submitted each year about new monodose or multidose DPI devices.
  • Monodose and multidose devices each present their own advantages and the final choice for administering the drug via one or the other kind of device is influenced by a large number of parameters as listed hereinbelow: TABLE 2 Characteristics of the ideal DPI device 1. High lung deposition of the drug (with low deposition in the oro- pharynx and low losses in the device itself) 2.
  • the present invention only relates to monodose DPI devices working with capsules.
  • the single dose DPI devices working with capsules usually possess a system to pierce the capsule. After the piercing, the patient inhales the powder contained in the capsule through the device without swallowing the capsule. The capsule remains in the device (and is consequently not swallowed by the patient).
  • the capsule should be entirely empty after inhalation. It is the object of the present invention to improve the emptying of the HPMC capsules by the use of a device equipped with piercing pins having a diameter of at least 0.8 mm, said pins being preferably bevel-edged.
  • the present invention relates to an improved inhalation pharmaceutical composition consisting of (A) a dry powder formulation containing a micronized active ingredient, alone or mixed with an inactive ingredient, said powder being filled in a hydroxypropylmethylcellulose (HPMC) container or capsule, said container having an outer surface extending between two end portions intended to be pierced or perfored, and (B) a dry powder inhaler device, advantageously a single dose dry powder inhaler device adapted to said capsule and equipped with at least one piercing pin having an equivalent diameter of not less than 0.8 mm.
  • HPMC hydroxypropylmethylcellulose
  • the piercing pin(s) has an equivalent diameter lower than 3 mm, preferably lower than 2 mm.
  • the equivalent diameter of the pin is determined at the section of the pin causing the larger hole in the envelope.
  • the equivalent diameter of said section corresponds to 4 times the cross section area of said section divided by the outer perimeter of said cross section area, wherein the cross section area is determined in a plane perpendicular to the direction of movement of the pin.
  • the pin is a rod provided with a shaped cutting or piercing end
  • the equivalent diameter corresponds to the diameter of the rod.
  • the cross section area of said section is advantageously circular or substantially circular, but can also be square, rectangular, elliptic, hexagonal, octahedral, pentagonal, etc.
  • the cross section area of said section is of at least 1.5 mm 2 , preferably at least about 1.9 mm 2 , such as about 2 mm 2 , 2.5 mm 2 , 3 mm 2 , etc.
  • the piercing systems are bevel-edged needles or pins. This enables an easier piercing of the envelope, even if the diameter of the piercing pin is larger.
  • the dry powder inhaler is advantageously equipped with at least two advantageously substantially identical piercing systems, adapted to pierce or perfore said container at said two end portions, said piercing systems having an equivalent diameter of not less than 0.8 millimeter (mm), preferably not less than 1 mm, whereby the piercing systems are adapted so that the equivalent diameter of the hole or holes pierced by each piercing system (after removal of the piercing system from the holes) is from 10 to 31%, and preferably from 15% to 26% of the equivalent diameter (advantageously the equivalent inner diameter) of the cross section of the portion of the outer surface of the container (of the hollow or room defined by said outer surface) to be pierced located between the two pierced end portions, said cross section being located in a plane perpendicular to an axis extending between the end portions, advantageously a symmetrical axis extending between the end portions.
  • the improved dry powder inhalation system of the invention comprises:
  • the number of said piercing systems per device is less than 8, preferably less than 5, more preferably less than 3. Most preferably, the number of piercing systems is 1 or 2, 2 being the most preferred number.
  • the active ingredient is advantageously mixed with pharmaceutical acceptable carrier before being filled in said container.
  • Said pharmaceutical acceptable carrier is advantageously a mono- or dissacharide derivative and/or a lactose.
  • the weight mean size of the micronized active(s) ingredient(s) is advantageously below 10 ⁇ m, preferably below 8 ⁇ m and most preferably below 6 ⁇ m. Most preferably, the weight average particle size of the active ingredient is comprised between 0.5 ⁇ m and 5 ⁇ m. According to an embodiment, the capsule contains substantially no particles with a particle size of less than 0.4 ⁇ m.
  • the micronized active ingredient is from the class of mucolytics, bronchodilators, corticosteroids, xanthine derivatives, leukotriene antagonists, proteins or peptides, and mixtures thereof.
  • the active ingredient is L-lysine N-acetylcysteinate.
  • dry powder composition can contain two or more active ingredients.
  • the invention relates also to the use of a hydroxypropylmethylcellulose capsule for the preparation of a dosage form containing a dry powder of at least one therapeutic active agent to be administered by inhalation after having pierced holes, each hole having an open passage of at least 1.5 mm 2 , preferably at least 2 mm 2 , most preferably at least 2.5 mm 2 in said hydroxypropylmethylcellulose capsule.
  • the dry powder inhalation system comprises at least one bucal or nasal piece and one basal piece adapted for containing the capsule, said basal piece being equipped with two pins and at least a means for actuating or moving said pins towards the envelope to be pierced.
  • the means for moving the two pins is advantageously pressing buttons operating the pins.
  • the invention further relates to:
  • FIG. 1 is a schematic view (with cross section) of a four pin device
  • FIG. 2 is a schematic view with cross section of a “single pin device” of the invention
  • FIGS. 3 and 4 are longitudinal side views of a pin of the device of FIG. 2 .
  • FIG. 5 is an upper view of the basal element of the device of FIG. 2 .
  • FIG. 6 is a cross section view of the basal element of the FIG. 5 along the line VI-VI,
  • FIG. 7 is a view similar to the FIG. 6 showing the movement of the two pins
  • FIG. 8 is a schematic view of a pierced envelope
  • FIG. 9 is a cross section view of the pierced envelope of FIG. 8 .
  • FIG. 10 shows a comparison of various FPD, namely the FPD of budesonide/salmeterol 200/25 ⁇ g DPI combinations+single pin device versus the FPD obtained Serevent® Diskus® 50 ⁇ g and Pulmicort® Turbohaler 200 ⁇ g (MLI).
  • the average particle size (average in weight) is less than 10 ⁇ m, advantageously less than 8 ⁇ m, preferably less than 6 ⁇ m.
  • the weight average particle size is comprised between 0.5 ⁇ m and 6 ⁇ m, preferably lower than 5 ⁇ m, most preferably lower than 4 ⁇ m, such as about 2 ⁇ m, about 3 ⁇ m.
  • the average (average in weight) particle size of the active agent containing powder is about 3 ⁇ m, with at least 50% by weight of the particles have a size comprised between about 2 ⁇ m and about 4 ⁇ m.
  • the importance of obtaining a high and reproducible dose of the active substance in the lungs are multiple.
  • the lung deposition may allow to reduce the nominal dose of the drug substance and decreasing the amount of drug absorbed in the systemic circulation and also potentially decrease the side-effects of the drug. This is especially true for corticosteroids and long acting ⁇ -2 mimetics which present potentially serious side-effects.
  • the fact to dispose of a DPI system reliable i.e. able to deliver a reproducible dose to the lung is of primary importance for the efficacy of the product in the long term and for the patients to feel reassured about their treatment.
  • DPI formulations may contain only the micronized active ingredient or the micronized active ingredient mixed with one or more inactive ingredients.
  • the main role of the inactive ingredient is to improve the flowability and the delivery of the dry powder.
  • HPMC capsules for inhalation
  • a European patent application (EP 0606486) has been submitted claiming their possible use in inhaled formulation because of their lower adherence than hard gelatin capsules.
  • Tests made by applicant have shown that when using conventional dry inhalation system with conventional piercing system, after inhalation, the amount of drug still present in the HPMC capsule (about 20% of the drug initially present in the capsule) was substantially equal to the amount of drug still present in the gelatine capsule (about 18% of the drug initially present in the capsule).
  • Tests made by Applicant have also shown that when using a conventional inhaler system, the lung deposition was better when using a gelatin capsule, instead of a HPMC capsule
  • HPMC capsules are not a sufficient condition to obtain better performances than hard gelatin capsules with DPI formulations.
  • the performances in term of lung deposition of the drug may lower with HPMC capsules than with hard gelatin capsules if the device used for administering the drug is not adapted at the same time.
  • the invention relates principally to the improved lung deposition as quantified by the Fine Particle Dose (FPD) with a combination of (A) a micronized active ingredient mixed or not with excipients, and contained in HPMC capsules and (B) a single dose dry powder inhaler device equipped with at least one piercing pin having a diameter of at least 0.8 mm.
  • FPD Fine Particle Dose
  • the new adapted single dose DPI device is derived from a previous patented device (U.S. Pat. No. 3,991,761).
  • the DPI device described in U.S. Pat. No. 3,991,761 contains (A) a mouthpiece, (B) a capsules chamber where the capsule is inserted before inhalation and (C) a perforating system constituted of four pins (or needles) at each end of the capsule chamber in order to perforate 8 holes in the capsules (4 holes at each end of the capsule). Those pins are operated or moved by pressing buttons 1 located at the exterior part of the capsules chamber. The diameter of the 8 piercing pins of this device is of 0.6 ⁇ 0.1 mm.
  • a Figure representing this device is given schematically in FIG. 1 with the cap (D) removed or in open position. In the present specification, this device will be called the “four pins device”. This device is not a device suitable for the combination of the invention.
  • the single dose device of the present invention is derived from the four pin device.
  • the four pins of diameter of 0.6 ⁇ 0.1 mm at both ends of the capsule chamber were replaced by a single pin at each end of the capsule chamber (2 pins in total) but with a larger diameter 1.2 ⁇ 0.1 mm Those bigger pins are bevel-edged in order to allow an easier penetration of the pins in the capsules while the pins of the “four pins device” are “nail-shaped”.
  • the single dose device of the present invention with two opposite pins one for piercing a first end of the capsule and another for piercing the opposite end of the capsule
  • the single pin device is schematically represented in FIG. 2 , said device corresponding to the device of FIG. 1 , except that each button 1 is provided with a single larger piercing pin 2 , instead of four smaller piercing pins.
  • the diameter of the hole made by the piercing pin in hard gelatin or HPMC material is always smaller than the diameter of the pin itself because of the elastic properties of the capsules material, which is responsible for some retraction of the holes after piercing.
  • the diameter of the hole observed in the HPMC capsule after piercing is of approximately 1 mm.
  • the present invention does not relate to a specific kind of device as such, but to the advantageous combination of a specific device and a specific powder container resulting in an optimal inhalation system.
  • the device of FIG. 2 comprises a mouth piece 4 with a substantially oval end attached to a base element 3 , a cap D being provided for covering the mouth piece when the device is not used for inhalation.
  • the base element 3 comprises a central chamber B adapted for receiving a HPLC capsule, said chamber having a form and a volume greater than the capsule, so as to enable a movement of the capsule during the inhalation.
  • the base element is provided with two opposite recesses 4 , each recess communicating with the chamber B by a channel 5 .
  • Each recess is associated to a button 1 bearing a pin 2 , the free end is partly engaged in the channel 5 when the button is not operated.
  • the buttons are each operated against the action of a return mechanism, such as a spring 6 . When the buttons are pressed the one towards the other, the free end of each pin 2 enters the chamber B so as to contact a capsule placed in said chamber and so as to pierce said capsule. After piercing, the return mechanism enables the movement of the free end of the pin 2 outside of the pierced capsule.
  • the base element is also provided with means for entering inhalation air in the device. Said air enters the base through the openings 7 and is guided in and/or above the chamber B so as to put into movement (such as rotation) the capsule and so as to aspire the particle and to move them towards the mouth piece A.
  • the DPI device works as follows: the patient opens the device, inserts a capsule in the capsule chamber, closes the device, pushes the buttons in order to pierce the capsule and finally the patient puts the mouthpiece of the device in its mouth and inhales deeply.
  • the capsules begins to rotate on itself, so allowing the powder to go outside the capsule via the eight holes pierced by the device of FIG. 1 or two holes in the case of the single pin device of FIG. 2 and, via the mouthpiece, to reach the patient's respiratory tract.
  • FIGS. 3 and 4 are enlarged longitudinal views of a pin 2 used in the device of FIG. 1 .
  • the views are a vertical longitudinal view and a horizontal longitudinal view.
  • the pin 2 is provided with a shaped cutting free end 2 A.
  • Said end 2 A is provided with an inclined or beveled surface 2 B extending between two opposite longitudinal portions (upper and lower portions) 2 C, 2 D of the pin, the angle formed by said surface with respect to the portion 2 C, 2 D being for example comprised between 15 and 75°.
  • the inclined surface is provided to with cutting edges 2 E, 2 F connected in the prolongation of the portion 2 D by a sharp pointed edge 2 G.
  • FIG. 8 shows on an enlarged scale the piercing or perforation of an envelope HPMC 10 .
  • the envelope 10 is provided with two opposite openings 11 , 12 extending substantially along a longitudinal axis 13 of the envelope.
  • the piercing has been made by using two pin as disclosed in FIGS. 3 and 4 .
  • the cutting edges 2 E, 2 F form a cutting, while the beveled or inclined surface 2 B pushes the cut area of the capsule into the inner space of the capsule, so as to form a small inner guiding surface 14 , 15 associated to each opening 11 , 12 .
  • the diameter DH of the substantially circular opening 11 and 12 corresponds to about 20 to 25% of the inner diameter DI of the longitudinal portion (cylindrical) 10 A of the capsule located between the curved ends 10 B, 10 C, or to about 19 to 24% of the outer diameter DE of the central portion 10 A of the capsule 10 .
  • Examples of possible capsules are with a size 1, 2 and 3 (for example Vcaps TM), size 2 and 3 being more preferred.
  • the total length of the capsule is for example comprised between 15 mm and 20 mm, while the outer diameter of the central portion 10 A is comprised between 5.5 mm and 7 mm, the thickness of the wall being about 100 ⁇ m.
  • the inner volume of the capsule is advantageously lower than 0.5 ml, such as 0.3 ml. A volume of about 0.3 ml seems to be quite appropriate.
  • the weight of the capsule without active ingredient i.e. the weight of the capsule as such is advantageously lower than 80 mg, preferably lower than 50 mg.
  • the total weight of the capsule with the powder to be inhaled is lower than 100 mg, most specifically lower than 75 mg.
  • the invention relates thus also to the use of pins as disclosed in FIGS. 3 and 4 for piercing a capsule (HPMC or not), as well as the use of two pins as shown in FIG. 8 for piercing a capsule (HPMC, gelatin, etc.), and finally also a pierced capsule as shown if FIGS. 8 and 9 .
  • Formoterol fumarate is a well known long acting bronchodilator used in the treatment of asthma.
  • Formoterol has been formulated in DPI with the formula given herebelow (Table 2) and then the powder was filled into either hard gelatin capsules or HPMC capsules.
  • the FPD of formoterol obtained from each type of capsule is given in Table 3. (The definition of the FPD is given in the European Pharmacopoeia, 3 rd edition, chapter 2.9.18. Briefly, the FPD is the dose (expressed in unity of mass) of the drug presenting a diameter below 5.0 ⁇ m when a formulation is tested on an Impactor)
  • the average (average in weight) particle size of the formoterol containing powder was about 3 ⁇ m (median Gauss range: about 2 to 4 ⁇ m, i.e. 50% by weight of the particles have a size comprised between about 2 ⁇ m and about 4 ⁇ m).
  • results obtained with the single pin device are different than those obtained with the four pins device, especially for HPMC capsules.
  • the FPD obtained from HPMC capsules+single pin device are higher than those obtained with hard gelatin capsules+single pin device.
  • the results obtained with the combination HPMC capsules+single pin device were significantly higher than the results obtained with HPMC capsules+four pin device.
  • Budesonide is a corticosteroid derivative very widely used in the treatment of asthma.
  • the formulations of budesonide tested are described in Table 4.
  • the average (average in weight) particle size of the micronized budesonide powder was about 3 ⁇ m (median Gauss range: about 2 to 4 ⁇ m, i.e. 50% by weight of the particles have a size comprised between about 2 ⁇ m and about 4 ⁇ m).
  • TABLE 5 formulation of budesonide DPI mg/capsule micronized budesonide 0.200 lactose 23.800 TOTAL: 24.00
  • the MMAD is the Mass Media Aerodynamic diameter.
  • MMAD is the diameter corresponding to 50% of the cumulative deposition obtained on the Multistage Liquid Impinger.
  • the GSD is the geometric standard deviation of the drug. All the calculations of those parameters have been realized in accordance with Eur. Ph., 3 rd , 2.9.18.
  • the lung deposition of the drug is optimal (high FPD and lower MMAD) when the DPI formulations are filled into HPMC capsules and administered with the single pin device.
  • Another consequence of the single pin device is the lower inter-test variability (lower SD), probably due to the fact that the hole pierced in the capsule with the single pin device is bigger, so allowing a more regular output of the powder from one capsule to the other
  • a DPI formulation containing 50 ⁇ g of salmeterol base (under the form of salmeterol xinafoate and 24.950 mg of lactose, has been filed into HPMC capsules.
  • a MLI test has been performed on those capsules administered with the single pin device and the results were compared to the results obtained with a marketed salmeterol DPI formulation of salmeterol (Serevent®, Diskus®, Glaxo Smithkline).
  • Each device was used at the airflow recommended by the European Pharmacopoeia 4 th edition i.e 100 L/min for the single pin device and 80 L/min for the Serevent® Diskus®.
  • a new combination containing 2 active ingredients i.e. budesonide and salmeterol xinafoate in the same DPI capsule has also been tested and compared to the existing DPI formulations of each active ingredient i.e. Pulmicort® Turbuhaler 200 ug (Astra Zeneca) for budesonide and Serevent® Diskus 50 ⁇ g for salmeterol xinafoate.
  • the HPMC capsule filled with this powder blend was tested on the MLI apparatus using the single dose device of the present invention.
  • FIG. 10 shows a comparison of various FPD, namely the FPD of budesonide/salmeterol 200/25 ⁇ g DPI combinations+single pin device versus Serevent® Diskus® 50 ⁇ g and Pulmicort® Turbuhaler 200 ⁇ g (MLI).
  • the FPD obtained for budesonide and salmeterol are significantly higher for the combination filled into HPMC capsules and administered with the single pin DPI device of the invention than for the respective marketed form of budesonide and salmeterol.
  • the invention also relates to the improvement of the chemico-physical stability of the DPI powder contained in the HPMC capsules in comparison with the stability obtained with DPI contained in hard gelatin capsules.
  • HPMC capsules This improvement in the chemico-physical stability of DPI powder in HPMC capsules is partially explained by the relatively low content in water of HPMC capsules (3-7%) in comparison with hard gelatin capsules (12-16%). That means that HPMC capsules may be theoretically advantageous for all active ingredients sensitive to moisture. In particular, proteins and active peptides may be advantageously formulated as DPIs using HPMC capsules.
  • the active ingredient is not chemically sensitive to moisture, it may advantageously be formulated as a DPI in HPMC capsules since the humidity contained in the capsule may also be responsible for agglomeration and/or hygroscopic particles growth, causing a diminution of the FPD and consequently a diminution of the dose available in the patient's lung.
  • HPMC capsules may be dried until they contain less than 0.5% of water without presenting any apparition of brittleness while hard gelatin capsules capsule became to break themselves when their content in water is below 10%.
  • the invention relates also to method of treatment a disease or for preventing troubles, in which a capsule of the invention is used for the administration of one or more active agents.
  • the method of the invention is for example a method for treating respiratory diseases and/or for preventing respiratory troubles.
  • one or more active ingredients are administered or deposited in the lung(s).
  • one or more active ingredients are administered or deposited in the systemic circulation.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pulmonology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Anesthesiology (AREA)
  • Hematology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Otolaryngology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Preparation (AREA)
  • Detergent Compositions (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Manufacturing Of Micro-Capsules (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US10/549,124 2003-03-20 2004-03-17 Dry powder inhaler system Abandoned US20060254583A1 (en)

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US14/642,134 US20150231344A1 (en) 2003-03-20 2015-03-09 Dry powder inhaler system

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WOPCT/BE03/00048 2003-03-20
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US20050150492A1 (en) * 2003-04-09 2005-07-14 Nektar Therapeutics Aerosolization apparatus with air inlet shield
US20070071689A1 (en) * 2003-08-06 2007-03-29 Galephar M/F Advantageous combination for inhalation of nacystelyn and bronchodilators
US20070107722A1 (en) * 2005-11-15 2007-05-17 Hubert Hoelz Needle for piercing a powder capsule for inhalation
US20070221216A1 (en) * 2006-03-10 2007-09-27 Ganem Charles F Medication inhaler
US20080092887A1 (en) * 2004-12-07 2008-04-24 Hodson Peter D Single-Dose Inhalation Devices
US20090090362A1 (en) * 2005-04-15 2009-04-09 Vectura Group Plc Blister piercing element for dry powder inhaler
US20090293873A1 (en) * 2005-02-23 2009-12-03 Optinose As Powder delivery devices
WO2009151408A2 (fr) 2008-05-16 2009-12-17 Bilgic Mahmut Dispositif d'inhalation facile à utiliser
US20100108062A1 (en) * 2006-03-10 2010-05-06 Dose One, Llc Medication inhaler
US20100313886A1 (en) * 2007-08-01 2010-12-16 Herbert Wachtel Inhaler
US20110056488A1 (en) * 2008-01-24 2011-03-10 Vectura Delivery Devices Limited Inhaler
US20110094507A1 (en) * 2008-01-24 2011-04-28 Vectura Delivery Devices Limited Inhaler
US20110220106A1 (en) * 2006-03-10 2011-09-15 Dose One, Llc Medication inhaler for dispensing multiple capsules
US20110220234A1 (en) * 2008-11-26 2011-09-15 Rouven Haas Apparatus for taking in powder material and granules and capsule therefor
US20130276783A1 (en) * 2010-12-17 2013-10-24 Qingtang Chen Filtering powder medicament inhaler and application
US8677992B2 (en) 2010-04-26 2014-03-25 Hovione International Ltd. Simple capsule-based inhaler
US8869794B1 (en) * 2003-04-09 2014-10-28 Novartis Pharma Ag Aerosolization apparatus with capsule puncturing member
US9108015B2 (en) 2004-09-15 2015-08-18 Optinose As Nasal delivery devices
USD752204S1 (en) 2014-03-10 2016-03-22 Civitas Therapeutics, Inc. Indicator for an inhaler
USD752734S1 (en) 2014-03-10 2016-03-29 Civitas Therapeutics, Inc. Inhaler grip
USD755367S1 (en) 2014-03-10 2016-05-03 Civitas Therapeutics, Inc. Indicator for an inhaler
US20170165439A1 (en) * 2014-03-10 2017-06-15 Inspiro Medical Ltd. Active dry powder inhaler
WO2018100461A1 (fr) * 2016-11-30 2018-06-07 Philip Morris Products S.A. Inhalateur avec bouchon d'extrémité de tourbillonnement
US10034989B2 (en) 2013-01-23 2018-07-31 Vectura Delivery Devices Limited Blister piercing element for a dry powder inhaler
CN108430551A (zh) * 2015-12-24 2018-08-21 菲利普莫里斯生产公司 尼古丁颗粒封壳
WO2018222581A1 (fr) * 2017-05-29 2018-12-06 Resinnate Therapeutics Llc Méthodes et formulations pour l'administration de bêta-glucane
CN109758653A (zh) * 2019-02-27 2019-05-17 浙江百安医疗科技有限公司 一种用于穿刺吸入粉雾剂胶囊的针及其给药装置
CN109922851A (zh) * 2016-11-30 2019-06-21 菲利普莫里斯生产公司 具有经大小设定的腔的吸入器
CN110709063A (zh) * 2017-06-28 2020-01-17 菲利普莫里斯生产公司 具有与吸入器一起使用的颗粒的容器
US20200197633A1 (en) * 2014-11-09 2020-06-25 Sipnose Ltd Bfs-ffs devices and methods for delivering a substance to a body cavity
US20200206440A1 (en) * 2017-08-31 2020-07-02 Pulinno Sp. Z O.O. An inhaler for a single-dose of dry powder and a method for adjusting an inhaler for single-dose of dry powder for delivering a specific medicament
CN115814218A (zh) * 2023-02-14 2023-03-21 杭州希溪制药有限公司 一种设有防分离结构的粉雾剂吸入器械
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US7559325B2 (en) 2003-04-09 2009-07-14 Novartis Pharma Ag Aerosolization apparatus with air inlet shield
US8869794B1 (en) * 2003-04-09 2014-10-28 Novartis Pharma Ag Aerosolization apparatus with capsule puncturing member
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US20070071689A1 (en) * 2003-08-06 2007-03-29 Galephar M/F Advantageous combination for inhalation of nacystelyn and bronchodilators
US10398859B2 (en) 2004-09-15 2019-09-03 Optinose As Nasal delivery devices
US9108015B2 (en) 2004-09-15 2015-08-18 Optinose As Nasal delivery devices
US20080092887A1 (en) * 2004-12-07 2008-04-24 Hodson Peter D Single-Dose Inhalation Devices
US20180272085A1 (en) * 2005-02-23 2018-09-27 Optinose As Powder Delivery Devices
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US9289564B2 (en) * 2005-04-15 2016-03-22 Vectura Delivery Devices Limited Blister piercing element for dry powder inhaler
US20090090362A1 (en) * 2005-04-15 2009-04-09 Vectura Group Plc Blister piercing element for dry powder inhaler
US20070107722A1 (en) * 2005-11-15 2007-05-17 Hubert Hoelz Needle for piercing a powder capsule for inhalation
US9604017B2 (en) 2005-11-15 2017-03-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Needle for piercing a powder capsule for inhalation
US8360057B2 (en) 2006-03-10 2013-01-29 Dose One, Llc Medication inhaler for dispensing multiple capsules
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US20110220106A1 (en) * 2006-03-10 2011-09-15 Dose One, Llc Medication inhaler for dispensing multiple capsules
US8464712B2 (en) * 2006-03-10 2013-06-18 Dose One, Llc Medication inhaler
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US9295792B2 (en) 2008-01-24 2016-03-29 Vectura Delivery Devices Limited Inhaler
US20110094507A1 (en) * 2008-01-24 2011-04-28 Vectura Delivery Devices Limited Inhaler
US9125998B2 (en) * 2008-01-24 2015-09-08 Vectura Delivery Devices Limited Inhaler
WO2009151408A2 (fr) 2008-05-16 2009-12-17 Bilgic Mahmut Dispositif d'inhalation facile à utiliser
US20110220234A1 (en) * 2008-11-26 2011-09-15 Rouven Haas Apparatus for taking in powder material and granules and capsule therefor
US8677992B2 (en) 2010-04-26 2014-03-25 Hovione International Ltd. Simple capsule-based inhaler
US9339614B2 (en) * 2010-12-17 2016-05-17 Qingtang Chen Filtering powder medicament inhaler and application
US20130276783A1 (en) * 2010-12-17 2013-10-24 Qingtang Chen Filtering powder medicament inhaler and application
US10034989B2 (en) 2013-01-23 2018-07-31 Vectura Delivery Devices Limited Blister piercing element for a dry powder inhaler
US10166350B2 (en) * 2014-03-10 2019-01-01 Inspiro Medical Ltd. Active dry powder inhaler
US20170165439A1 (en) * 2014-03-10 2017-06-15 Inspiro Medical Ltd. Active dry powder inhaler
USD752204S1 (en) 2014-03-10 2016-03-22 Civitas Therapeutics, Inc. Indicator for an inhaler
USD752734S1 (en) 2014-03-10 2016-03-29 Civitas Therapeutics, Inc. Inhaler grip
USD755367S1 (en) 2014-03-10 2016-05-03 Civitas Therapeutics, Inc. Indicator for an inhaler
US11992604B2 (en) * 2014-11-09 2024-05-28 Sipnose Ltd. Devices and methods for delivering a substance to a body cavity
US20200197633A1 (en) * 2014-11-09 2020-06-25 Sipnose Ltd Bfs-ffs devices and methods for delivering a substance to a body cavity
CN108430551A (zh) * 2015-12-24 2018-08-21 菲利普莫里斯生产公司 尼古丁颗粒封壳
CN109922851A (zh) * 2016-11-30 2019-06-21 菲利普莫里斯生产公司 具有经大小设定的腔的吸入器
KR20190089857A (ko) 2016-11-30 2019-07-31 필립모리스 프로덕츠 에스.에이. 소용돌이 단부 플러그를 갖는 흡입기
US11471622B2 (en) 2016-11-30 2022-10-18 Philip Morris Products S.A. Inhaler with swirl end plug
WO2018100461A1 (fr) * 2016-11-30 2018-06-07 Philip Morris Products S.A. Inhalateur avec bouchon d'extrémité de tourbillonnement
WO2018222581A1 (fr) * 2017-05-29 2018-12-06 Resinnate Therapeutics Llc Méthodes et formulations pour l'administration de bêta-glucane
US11690964B2 (en) 2017-05-31 2023-07-04 Virginia Commonwealth University Devices, systems, and methods for dry powder therapies
CN110709063A (zh) * 2017-06-28 2020-01-17 菲利普莫里斯生产公司 具有与吸入器一起使用的颗粒的容器
US20200206440A1 (en) * 2017-08-31 2020-07-02 Pulinno Sp. Z O.O. An inhaler for a single-dose of dry powder and a method for adjusting an inhaler for single-dose of dry powder for delivering a specific medicament
CN109758653A (zh) * 2019-02-27 2019-05-17 浙江百安医疗科技有限公司 一种用于穿刺吸入粉雾剂胶囊的针及其给药装置
CN115814218A (zh) * 2023-02-14 2023-03-21 杭州希溪制药有限公司 一种设有防分离结构的粉雾剂吸入器械

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CA2519228A1 (fr) 2004-09-30
DE602004014909D1 (de) 2008-08-21
ATE400313T1 (de) 2008-07-15
CA2519228C (fr) 2014-10-14
US20100300440A1 (en) 2010-12-02
EP1603615B1 (fr) 2008-07-09
PL1603615T3 (pl) 2009-01-30
ES2310722T3 (es) 2009-01-16
WO2004082750A1 (fr) 2004-09-30
EP1603615A1 (fr) 2005-12-14
US20150231344A1 (en) 2015-08-20

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